“Regulation of subcelluar distribution of cytosolic ribonucleoparticles and translation factors during the cellular response to stress”

LOSCHI, MARIELA; BOCCACCIO, GRACIELA L

Dubrovnik, Croacia,

Congreso; FEBS meeting “Cellular Signaling”; 2006

FEBS

Regulation of subcelluar distribution of cytosolic ribonucleoparticles and translation factors during the cellular response to stress. Loschi, M and Boccaccio GL Fundación Instituto Leloir, IIBBA-CONICET; IIB-FCEyN-University of Buenos Aires. mloschi@leloir.org.ar     Under cellular stress (e.g. heat, oxidative agents, UV, etc) protein translation is inhibited by the phosphorylation of the eukaryotic initiation factor eIF2alpha. This leads to the accumulation of stalled translational preinitiation complexes that agregates in the cytoplasm along with a number of RNA-binding proteins (TIA-1/R, HuR, Staufen, etc) forming novel structures named Stress Granules (SGs). SGs are proposed to serve as a triage site that controls the fate of untranslated mRNAs. The change in the subcellular distribution of the translational machinery and ribonucleoparticles (RNPs) that occurs upon stress implies an active transport that we are aimed to investigate. To asses the participation of molecular motors in the repositioning of translation factors and RNPs under stress conditions the effect of drugs that specifically disassemble microtubules or microfilaments was assessed. In the absence of microtubules, non-perinuclear SGs showing a quite normal size were observed, whereas in the absence of microfilaments, small and scattered SGs were formed. These results suggest that molecular motors, both microtubule dependent (kinesins and/or dyneins) and microfilament dependent ones (myosins) maybe involved in the formation of stress granules. Consistently whits this, we found a strong immnuofluorescence signal in stress granules for Myosin Va and Kinesin I/KIF5. The working hypothesis to test is that the balance between anterograde and retrograde transport of RNPs, driven by kinesins and dyneins respectively, is modulated during the stress response, allowing accumulation of mRNPs in the perinuclear regions. The rapid cell response induced by stressors largely depends on phosphorylation cascades. Relevantly, the interaction of motor molecules with their cargo as well as the ATPase activity of the motor domain have been reported to be regulated by phosphorylation.  Our final goal is to identify the signaling cascades involved in the regulation of the motor molecules activity.